Skip to main content

Advertisement

SpringerLink
Log in

Blocking the PI3K pathway enhances the efficacy of ALK-targeted therapy in EML4-ALK-positive nonsmall-cell lung cancer

  • Research Article
  • Published:
Tumor Biology

Abstract

Targeted therapy based on ALK tyrosine kinase inhibitors (ALK-TKIs) has made significant achievements in individuals with EML4-ALK (echinoderm microtubule-associated protein-like 4 gene and the anaplastic lymphoma kinase gene) fusion positive nonsmall-cell lung cancer (NSCLC). However, a high fraction of patients receive inferior clinical response to such treatment in the initial therapy, and the exact mechanisms underlying this process need to be further investigated. In this study, we revealed a persistently activated PI3K/AKT signaling that mediates the drug ineffectiveness. We found that genetic or pharmacological inhibition of ALK markedly abrogated phosphorylated STAT3 and ERK, but it failed to suppress AKT activity or induce apoptosis, in EML4-ALK-positive H2228 cells. Furthermore, targeted RNA interference of PI3K pathway components restored sensitivity to TAE684 treatment at least partially due to increased apoptosis. Combined TAE684 with PI3K inhibitor synergistically inhibited the proliferation of EML4-ALK-positive cells in vitro and significantly suppressed the growth of H2228 xenografts in vivo, suggesting the potential clinical application of such combinatorial therapy regimens in patients with EML4-ALK positive lung cancer.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Iwahara T, Fujimoto J, Wen D, Cupples R, Bucay N, Arakawa T, et al. Molecular characterization of ALK, a receptor tyrosine kinase expressed specifically in the nervous system. Oncogene. 1997;14:439–49.

    Article  CAS  PubMed  Google Scholar 

  2. Morris SW, Kirstein MN, Valentine MB, Dittmer K, Shapiro DN, Look AT, et al. Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin's lymphoma. Science. 1995;267:316–7.

    Article  CAS  PubMed  Google Scholar 

  3. Soda M, Choi YL, Enomoto M, Takada S, Yamashita Y, Ishikawa S, et al. Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature. 2007;448:561–6.

    Article  CAS  PubMed  Google Scholar 

  4. Horn L, Pao W. EML4-ALK: honing in on a new target in non-small-cell lung cancer. J Clin Oncol. 2009;27:4232–5.

    Article  CAS  PubMed  Google Scholar 

  5. Schulte JH, Bachmann HS, Brockmeyer B, Depreter K, Oberthur A, Ackermann S, et al. High ALK receptor tyrosine kinase expression supersedes ALK mutation as a determining factor of an unfavorable phenotype in primary neuroblastoma. Clin Cancer Res. 2011;17:5082–92.

    Article  CAS  PubMed  Google Scholar 

  6. Ogawa S, Takita J, Sanada M, Hayashi Y. Oncogenic mutations of ALK in neuroblastoma. Cancer Sci. 2011;102:302–8.

    Article  CAS  PubMed  Google Scholar 

  7. Murugan AK, Xing M. Anaplastic thyroid cancers harbor novel oncogenic mutations of the ALK gene. Cancer Res. 2011;71:4403–11.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  8. Christensen JG, Zou HY, Arango ME, Li Q, Lee JH, McDonnell SR, et al. Cytoreductive antitumor activity of PF-2341066, a novel inhibitor of anaplastic lymphoma kinase and c-Met, in experimental models of anaplastic large-cell lymphoma. Mol Cancer Ther. 2007;6:3314–22.

    Article  CAS  PubMed  Google Scholar 

  9. Galkin AV, Melnick JS, Kim S, Hood TL, Li N, Li L, et al. Identification of NVP-TAE684, a potent, selective, and efficacious inhibitor of NPM-ALK. Proc Natl Acad Sci U S A. 2007;104:270–5.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  10. Doebele RC, Pilling AB, Aisner DL, Kutateladze TG, Le AT, Weickhardt AJ, et al. Mechanisms of resistance to crizotinib in patients with ALK gene rearranged non-small cell lung cancer. Clin Cancer Res. 2012;18:1472–82.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  11. Popat S, Vieira de Araujo A, Min T, Swansbury J, Dainton M, Wotherspoon A, et al. Lung adenocarcinoma with concurrent exon 19 EGFR mutation and ALK rearrangement responding to erlotinib. J Thorac Oncol. 2011;6:1962–3.

    Article  PubMed  Google Scholar 

  12. Dai Z, Kelly JC, Meloni-Ehrig A, Slovak ML, Boles D, Christacos NC, et al. Incidence and patterns of ALK FISH abnormalities seen in a large unselected series of lung carcinomas. Mol Cytogenet. 2012;5:44.

    Article  PubMed Central  PubMed  Google Scholar 

  13. Katayama R, Shaw AT, Khan TM, Mino-Kenudson M, Solomon BJ, Halmos B, et al. Mechanisms of acquired crizotinib resistance in ALK-rearranged lung Cancers. Sci Transl Med. 2012;4:120ra17.

    Article  PubMed Central  PubMed  Google Scholar 

  14. Chou TC, Talalay P. Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv Enzym Regul. 1984;22:27–55.

    Article  CAS  Google Scholar 

  15. Chou TC. Drug combination studies and their synergy quantification using the Chou-Talalay method. Cancer Res. 2010;70:440–6.

    Article  CAS  PubMed  Google Scholar 

  16. Kanaji N, Bandoh S, Ishii T, Tadokoro A, Watanabe N, Takahama T, et al. Detection of EML4-ALK fusion genes in a few cancer cells from transbronchial cytological specimens utilizing immediate cytology during bronchoscopy. Lung Cancer. 2012;77:293–8.

    Article  PubMed  Google Scholar 

  17. Li Y, Ye X, Liu J, Zha J, Pei L. Evaluation of EML4-ALK fusion proteins in non-small cell lung cancer using small molecule inhibitors. Neoplasia. 2011;13:1–11.

    Article  PubMed Central  PubMed  Google Scholar 

  18. Amin HM, Lai R. Pathobiology of ALK+ anaplastic large-cell lymphoma. Blood. 2007;110:2259–67.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  19. Tanizaki J, Okamoto I, Takezawa K, Sakai K, Azuma K, Kuwata K, et al. Combined effect of ALK and MEK inhibitors in EML4-ALK-positive non-small-cell lung cancer cells. Br J Cancer. 2012;106:763–7.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  20. Kwak EL, Bang YJ, Camidge DR, Shaw AT, Solomon B, Maki RG, et al. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med. 2010;363(18):1693–703.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  21. Camidge DR, Bang YJ, Kwak EL, Iafrate AJ, Varella-Garcia M, Fox SB, et al. Activity and safety of crizotinib in patients with ALK-positive non-small-cell lung cancer: updated results from a phase 1 study. Lancet Oncol. 2012;13(10):1011–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  22. McDermott U, Iafrate AJ, Gray NS, Shioda T, Classon M, Maheswaran S, et al. Genomic alterations of anaplastic lymphoma kinase may sensitize tumors to anaplastic lymphoma kinase inhibitors. Cancer Res. 2008;68(9):3389–95.

    Article  CAS  PubMed  Google Scholar 

  23. Koivunen JP, Mermel C, Zejnullahu K, Murphy C, Lifshits E, Holmes AJ, et al. EML4-ALK fusion gene and efficacy of an ALK kinase inhibitor in lung cancer. Clin Cancer Res. 2008;14:4275–83.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  24. Rikova K, Guo A, Zeng Q, Possemato A, Yu J, Haack H, et al. Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer. Cell. 2007;131:1190–203.

    Article  CAS  PubMed  Google Scholar 

  25. Chiarle R, Voena C, Ambrogio C, Piva R, Inghirami G. The anaplastic lymphoma kinase in the pathogenesis of cancer. Nat Rev Cancer. 2008;8:11–23.

    Article  CAS  PubMed  Google Scholar 

  26. Voena C, Di Giacomo F, Panizza E, D'Amico L, Boccalatte FE, Pellegrino E, et al. The EGFR family members sustain the neoplastic phenotype of ALK+ lung adenocarcinoma via EGR1. Oncogenesis. 2013;2:e43.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  27. Rodon J, Dienstmann R, Serra V, Tabernero J. Development of PI3K inhibitors: lessons learned from early clinical trials. Nat Rev Clin Oncol. 2013;10:143–53.

    Article  CAS  PubMed  Google Scholar 

  28. Hynes NE, Dey JH. PI3K inhibition overcomes trastuzumab resistance: blockade of ErbB2/ErbB3 is not always enough. Cancer Cell. 2009;15:353–5.

    Article  CAS  PubMed  Google Scholar 

  29. Ding J, Romani J, Zaborski M, MacLeod RA, Nagel S, Drexler HG, et al. Inhibition of PI3K/mTOR overcomes nilotinib resistance in BCR-ABL1 positive leukemia cells through translational down-regulation of MDM2. PLoS One. 2013;8:e83510.

    Article  PubMed Central  PubMed  Google Scholar 

  30. Donev IS, Wang W, Yamada T, Li Q, Takeuchi S, Matsumoto K, et al. Transient PI3K inhibition induces apoptosis and overcomes HGF-mediated resistance to EGFR-TKIs in EGFR mutant lung cancer. Clin Cancer Res. 2011;17:2260–9.

    Article  CAS  PubMed  Google Scholar 

Download references

Conflict of interest

None

Author information

Authors and Affiliations

  1. Department of Clinical Laboratory, Hubei Maternal and Child Health Hospital, Wuhan, 430070, China

    Lin Yang

  2. School of Bioscience and Bioengineering, South China University of Technology, Guangzhou, 510006, China

    Guangchao Li & Likun Zhao

  3. PLA General Hospital Cancer Center, PLA Postgraduate School of Medicine, Beijing, 100853, China

    Fei Pan

  4. School of Biology and Basic Medical Sciences, Soochow University, Suzhou, 215006, China

    Jiankun Qiang

  5. Department of Medical Oncology, Jinling Hospital, 305 Zhongshan North Road, Nanjing, 210002, China

    Siqi Han

Authors
  1. Lin Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Guangchao Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Likun Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Fei Pan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jiankun Qiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Siqi Han
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Siqi Han.

Additional information

Lin Yang and Guangchao Li contributed equally to this work and are joint first authors.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yang, L., Li, G., Zhao, L. et al. Blocking the PI3K pathway enhances the efficacy of ALK-targeted therapy in EML4-ALK-positive nonsmall-cell lung cancer. Tumor Biol. 35, 9759–9767 (2014). https://doi.org/10.1007/s13277-014-2252-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13277-014-2252-y

Keywords

Search

Navigation